Rifaximin, chemically known as {(2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-α]-benzimidazole-1,15(2H)-dione, 25-acetate} represented by formula I, is a semisynthetic rifamycin-based non-systemic antibiotic. It is marketed in the US as Xifaxan™ by Salix Pharmaceuticals.

It is useful for the treatment of travellers' diarrhoea in adults and in children 12-years or more of age caused by E. coli bacteria. Rifaximin has also been evaluated for the treatment of irritable bowel syndrome, diverticular disease, hepatic encephalopathy, pyogenic skin infections, and as an antibacterial prophylactic prior to colon surgery.
Structurally rifaximin is a pyrido-imidazo derivative of 4-deoxy-4′-methylpyrido[1′,2′:1,2]imidazo[5,4-c]rifamycin SV (Rifamycin SV). Unlike other Rifamycin SV derivatives, rifaximin exerts broad spectrum activity and has a specific mode of action which results in low gastrointestinal absorption.
GB 2079270 discloses imidazo-rifamycin derivatives having antibacterial activity, prepared from 3-halorifamycin S. U.S. Pat. No. 4,341,785 and EP 0161534 describe the processes for preparation of pyrido-imidazo rifamycin starting from rifamycin O. These patents describe a method for the purification of rifaximin using solvent systems comprising methylene chloride, chloroform, methanol, ethanol, isopropanol and water as an anti-solvent without disclosing the polymorphic form of the obtained Rifaximin.
U.S. Pat. No. 7,045,620 describes three polymorphic forms of rifaximin named as α-, β-, and γ-form. These forms are characterised by the different water contents and different 2θ values in powder X-ray diffractogram (PXRD) analysis. These forms are inter-convertible and, therefore, obtaining a specific polymorphic form is dependent on the drying conditions. The γ-form of U.S. Pat. No. 7,045,620 is described as poorly crystalline with a high content of amorphous component. It is characterized by water content between 1.0% and 2.0% and having a PXRD diffractogram containing three significant 2θ peaks at 5.0, 7.1 and 8.4. This form is prone to conversion to other polymorphic forms on exposure to atmosphere due to the change in its water content level. Thus this form is not preferred for formulation and it is highly desirable to have an active pharmaceutical ingredient which is polymorphically stable and suitable for pharmaceutical applications.
EP1698630 reported two new polymorphic forms δ- and ε-forms which are crystalline and there is a significant degree of overlap with the other reported forms.
U.S. Pat. No. 7,709,634 reported an amorphous form of rifaximin having two PXRD peaks at 2θ values 7.2° and 15.0°. This patent also discloses a process for its preparation by dissolving crude rifaximin in a solvent, precipitation by adding antisolvent, isolating and drying. This process uses preferably heptanes and methyl Tertiary butyl ether (MTBE) as an antisolvent.
U.S.2009/0312357 describes an amorphous rifaximin and its preparation. This amorphous rifaximin is prepared by stirring the crude rifaximin with a mixture of 20% dichloromethane and heptane at room temperature for 30-45 minutes and further washing with mixture of 20% dichloromethane and heptanes and drying under vacuum below 40° C. This process also uses multiple antisolvent.
Thus it is highly desirable to prepare a stable polymorphic form of rifaximin which is suitable for pharmaceutical formulation and prepared without using water or an antisolvent. The present inventors have developed a process which is robust and avoids water and antisolvent for preparing a novel amorphous rifaximin, which is stable chemically and polymorphically on storage and is unaffected by external parameters such as ambient humidity.